Abstract
Extracellular vesicles (EVs) are small membrane vesicles secreted by most cell types with important roles in cell-to-cell communication. To assess their relevance in the context of heart ischemia, EVs isolated from the AC10 ventricular cardiomyocyte cell line (CM-EVs), exposed to normoxia (Nx) or hypoxia (Hx), were incubated with fibroblasts (Fb) and endothelial cells (EC). CM-EVs were studied using electron microscopy, nanoparticle tracking analysis (NTA), western blotting and proteomic analysis. Results showed that EVs had a strong preference to be internalized by EC over fibroblasts, suggesting an active exosome-based communication mechanism between CM and EC in the heart. In Matrigel tube-formation assays, Hx CM-EVs were inferior to Nx CM-EVs in angiogenesis. By contrast, in a wound-healing assay, wound closure was faster in fibroblasts treated with Hx CM-EVs than with Nx CM-EVs, supporting a pro-fibrotic effect of Hx CM-EVs. Overall, these observations were consistent with the different protein cargoes detected by proteomic analysis under Nx and Hx conditions and the biological pathways identified. The paracrine crosstalk between CM-EVs, Fb, and EC in different physiological conditions could account for the contribution of CM-EVs to cardiac remodeling after an ischemic insult.
Highlights
Cardiac muscle is a highly adaptable tissue that responds to physiological challenges, in part, by releasing paracrine factors including extracellular vesicles (EVs) [1]
CM-Extracellular vesicles (EVs) secreted in Nx conditions contained protein cargo involved in extracellular matrix (ECM) organization, integrin-signaling, collagen catabolism, and cell adhesion and cell migration, whereas additional biological processes were over-represented in Hx CM-EVs, such as protein folding and peptide cross-linking, including pathways involved in chaperone activity and protein synthesis (Figure 1E)
We found that both Nx- and Hx-derived CMEVs were loaded with ECM components including different types of collagens and laminins, which are typically secreted by interstitial cells to modulate normal cardiac growth and remodeling
Summary
Cardiac muscle is a highly adaptable tissue that responds to physiological challenges, in part, by releasing paracrine factors including extracellular vesicles (EVs) [1]. Exosomes are small nanomembranous extracellular vesicles (30–150 nm in diameter) that contain a variety of molecules including cytokines, membrane trafficking molecules, chemokines, heat shock proteins, and several types of RNA molecules. Due to their diverse cargo, exosomes play a central role in cell-to-cell communication and we and others have previously examined the role of cardiomyocyte-derived exosomes (CM-Exo) in different stress conditions, such as glucose starvation [2], inflammation [3, 4] or ethanol treatment [5]. Our results shed more light on the contribution of CM-EVs to cardiac remodeling
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